The goal of this project is to identify novel chemical compounds that are active against the blood and liver stage forms of malaria parasites and that are useful for both prophylaxis and treatment of Plasmodium vivax and Plasmodium falciparum infections. Malaria has been identified as one of the most significant threats to deployed troops worldwide. This disease is endemic to Southwest Asia including Afghanistan, Southeast Asia, Africa, the Middle East, the Pacific, and both Central and South America. The project team previously completed high-throughput screening more than 400,000 compounds against the Dd2 strain of P. falciparum asexual blood stage parasite, and during this period, the team worked to identify compounds that selectively inhibited P. berghei liver stage parasites in vitro at submicromolar concentrations. An in-depth hit-to-lead campaign has since been initiated with a prioritized list of chemotypes, with the goal of identifying compounds that are potent in vitro against P. falciparum asexual blood stages and P. berghei liver stages. Potential lead molecules will be profiled to assess activity in the primary and secondary assays, as well as in pharmacological profiles to assess metabolic stability, solubility and membrane permeability. Two of the identified lead chemotypes were further optimized using medicinal chemistry leading to compounds with increased potency and pharmacokinetic properties. In addition to these initial hits, additional compounds with activity against the hyponozoite stage (dormant liver forms) have been identified, validation as well as initial structure-activity relationship utilizing existing analogs in currently underway.